Substituted aminoalkylaminopyridines

ABSTRACT

Compounds of formula I ##STR1## wherein R1, R2, R3, R4, R5, R6, X, n and A have the meanings as given in the description, can be used for combatting Helicobacter bacteria.

This application is a 371 of PCT/EP94/03911 filed on Nov. 26, 1994.

AREA OF APPLICATION OF THE INVENTION

The invention relates to compounds which are intended to be used in thepharmaceutical industry as active substance for the production ofpharmaceuticals.

KNOWN TECHNICAL BACKGROUND

International Patent Application WO92/12976 describes2-(pyridylmethylthio- and -sulfinyl)benzimidazoles which are substitutedin a particular manner and which are said to be active againsthelicobacter bacteria, and for which it is furthermore disclosed thatthey are intended to be suitable for preventing and treating a wholerange of gastric disorders.

DESCRIPTION OF THE INVENTION

The invention relates to compounds of formula I (see appended sheet offormulae) in which

R1 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, halogen, trifluoromethyl,wholly or predominantly fluorine-substituted 1-4C-alkoxy,chlorodifluoromethoxy or 2-chloro-1,1,2-trifluoroethoxy,

R2 is hydrogen or 1-4C-alkyl,

R3 is halogen or 1-4C-alkyl,

R4 is 1-7C-alkyl,

A is 1-7C-alkylene,

X is N or CH, and

n is the number 0, 1 or 2,

and in which

R5 is 1-7C-alkyl, 3-8C-cycloalkyl or Ar-1-4C-alkyl and

R6 is 1-7C-alkyl, 3-8C-cycloalkyl or Ar-1-4C-alkyl, where

Ar is phenyl, furyl, naphthyl, tetrahydronaphthyl, or phenyl which issubstituted by R7, R8 and R9,

or in which

R5 and R6 together represent, with inclusion of the nitrogen atom towhich both are bonded, an unsubstituted or substituted heterocyclic ringwhich is selected from the group consisting of pyrrolidine, piperidine,piperazine, morpholine, indoline, octahydro-1H-indole,1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline,decahydroquinoline and decahydroisoquinoline, where

a substituted pyrrolidino radical is substituted by one or two identicalor different substituents selected from the group consisting of

1-4C-alkyl,

1-4C-alkoxy,

1-4C-alkoxy-1-4C-alkyl,

1-4C-alkoxycarbonyl,

1-4C-alkylcarbonyloxy,

hydroxy-1-4C-alkyl,

hydroxyl and

carboxyl,

a substituted piperidino radical is substituted by one, two or threeidentical or different substituents selected from the group consistingof

1-4C-alkyl,

GEM.-di-1-4C-alkyl,

1-4C-alkoxy,

1-4C-alkoxy-1-4C-alkyl,

1-4C-alkoxycarbonyl,

1-4C-alkylcarbonyl,

1-4C-alkylcarbonyl-1-4C-alkyl,

hydroxy-1-4C-alkyl,

dihydroxy-1-4C-alkyl,

di-1-4C-alkylamino,

di-1-4C-alkylamino-1-4C-alkyl,

pyrrolidino,

piperidino,

pyrrolidinyl-1-4C-alkyl,

piperidinyl-1-4C-alkyl,

carbamoyl,

di-1-4C-alkylaminocarbonyl,

piperidinocarbonyl,

morpholinocarbonyl,

phenyl,

phenyl substituted by R7, R8 and R9,

phenyl-1-4C-alkyl,

benzoyl,

benzoyl substituted by halogen,

formyl,

carboxyl,

cyano,

hydroxyl,

halogen and

sulfo,

a substituted piperazino radical can be substituted in position 2, 3, 5or 6 by a 1-4C-alkyl radical and is substituted in position 4 by asubstituent selected from the group consisting of

1-4C-alkyl,

3-7C-cycloalkyl,

3-7C-cycloalkyl-1-4C-alkyl,

1-4C-alkoxycarbonyl,

1-4C-alkoxycarbonyl-1-4C-alkyl,

hydroxy-1-4C-alkyl,

di-1-4C-alkylamino-1-4C-alkyl,

halo-1-4C-alkyl,

carbamoyl,

phenyl,

phenyl substituted by R7, R8 and R9,

phenyl-1-4C-alkyl,

phenyl-1-4C-alkyl substituted by R7, R8 and R9 in the phenyl radical,

naphthyl,

benzhydryl and

benzhydryl substituted by halogen,

a substituted morpholino radical is substituted by one or two identicalor different 1-4C-alkyl radicals,

a substituted 1-indolinyl radical can be substituted in position 2and/or 3 by a carboxyl group or by one or two identical or different1-4C-alkyl radicals, and can be substituted in the benzo moiety by oneor two identical or different substituents selected from the groupconsisting of 1-4C-alkyl, halogen and nitro,

a substituted 1,2,3,4-tetrahydroquinoline radical is substituted by oneor two identical or different substituents selected from the groupconsisting of 1-4C-alkyl and halogen,

a substituted 1,2,3,4-tetrahydroisoquinoline radical can be substitutedon positions 1, 3 and/or 4 by one or two identical or differentsubstituents selected from the group consisting of 1-4C-alkyl, carboxyl,phenyl, phenyl-1-4C-alkyl or phenyl which is substituted by R7, R8 andR9 in the phenyl radical, and can be substituted on the benzo moiety byone or two substituents selected from the group consisting of hydroxyl,1-4C-alkoxy and di-1-4C-alkylamino, and where

R7 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkylcarbonyl, halogen,1-4C-alkylamino or nitro,

R8 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, halogen or nitro, and

R9 is hydrogen or trifluoromethyl,

and the salts of these compounds.

1-4C-Alkyl stands for straight-chain or branched alkyl radicals with 1to 4 carbon atoms. Examples which may be mentioned are the butyl,isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and methylradicals.

1-4C-Alkoxy stands for a radical which, besides the oxygen atom,contains one of the abovementioned 1-4C-alkyl radicals. Examples whichmay be mentioned are the methoxy and ethoxy radicals.

Halogen for the purpose of the present invention is bromine, chlorineand fluorine.

Examples of wholly or predominantly fluorine-substituted 1-4C-alkoxywhich may be mentioned are the 1,2,2-trifluoroethoxy, the2,2,3,3,3-pentafluoropropoxy, the perfluoroethoxy and, in particular,the 1,1,2,2-tetrafluoroethoxy, the trifluoromethoxy, the2,2,2-trifluoroethoxy and the difluoromethoxy radicals.

1-7C-Alkyl stands for straight-chain and branched alkyl radicals with 1to 7 carbon atoms. Examples which may be mentioned are the heptyl,hexyl, neopentyl, isopentyl, pentyl, butyl, isobutyl, sec-butyl,tert-butyl, propyl, isopropyl, ethyl and methyl radicals.

1-7C-Alkylene stands for straight-chain or branched 1-7C-alkyleneradical, for example the methylene (--CH₂ --), ethylene (--CH₂ --CH₂--), trimethylene (--CH₂ --CH₂ --CH₂ --), tetramethylene (--CH₂ --CH₂--CH₂ --CH₂), 1,2-dimethylethylene [--CH(CH₃)--], 1,1-dimethylethylene[--C(CH₃)₂ --CH₂ --], 2,2-dimethylethylene --CH₂ --C(CH₃)₂ --],isopropylidene [--C(CH₃)₂ --], 1-methylethylene [--CH(CH₃)CH₂ --],pentamethylene (--CH₂ --CH₂ --CH₂ --CH₂ --CH₂ --), hexamethylene (--CH₂--CH₂ --CH₂ --CH₂ --CH₂ --CH₂ --) and heptamethylene radicals (--CH₂--CH₂ --CH₂ --CH₂ --CH₂ --CH₂ --CH₂ --).

3-8C-Cycloalkyl stands for the cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl and cyclooctyl radicals.

Ar-1-4C-alkyl stands for one of the abovementioned Ar-substituted1-4C-alkyl radical. Examples which may be mentioned are the phenethyl,the benzyl, the 2-furylmethyl (═furfuryl) and the 1-naphthylmethylradicals.

1-4C-Alkoxy-1-4C-alkyl stands for one of the abovementioned 1-4C-alkylradicals which is substituted by one of the abovementioned 1-4C-alkoxyradicals. Examples which may be mentioned are the methoxymethyl, themethoxyethyl ethyl radicals and the butoxyethyl radical.

1-4C-Alkoxycarbonyl stands for a radical which, besides the carbonylgroup, contains one of the abovementioned 1-4C-alkoxy radicals. Exampleswhich may be mentioned are the methoxycarbonyl and the ethoxycarbonylradicals.

1-4C-Alkylcarbonyloxy stands for a radical which, besides thecarbonyloxy radical, contains one of the above 1-4C-alkyl radicals. Anexample which may be mentioned is the acetoxy radical.

Hydroxy-1-4C-alkyl stands for one of the abovementioned 1-4C-alkylradicals which is substituted by hydroxyl. Examples which may bementioned are the hydroxymethyl radical, the 2-hydroxyethyl radical orthe 3-hydroxypropyl radical.

1-4C-Alkylcarbonyl stands for a radical which, besides the carbonylgroup, contains one of the abovementioned 1-4C-alkyl radicals. Anexample which may be mentioned is the acetyl radical.

1-4C-Alkylcarbonyl-1-4C-alkyl stands for one of the abovementioned1-4C-alkyl radicals which is substituted by one of the abovementioned1-4C-alkylcarbonyl radicals. Examples which may be mentioned are the2-oxopropyl radical (acetonyl radical) and the 2-oxobutyl radical.

Dihydroxy-1-4C-alkyl stands for one of the abovementioned 1-4C-alkylradicals which is substituted by two hydroxyl groups. An example whichmay be mentioned is the 1,2-dihydroxyethyl radical.

Di-1-4C-alkylamino stands for an amino radical which is substituted bytwo identical or different abovementioned 1-4C-alkyl radicals. Exampleswhich may be mentioned are the dimethylamino, the diethylamino and thediisopropylamino radicals.

Di-1-4C-alkylamino-1-4C-alkyl stands for one of the abovementioned1-4C-alkyl radicals which is substituted by one of the abovementioneddi-1-4C-alkylamino radicals. Examples which may be mentioned are thedimethylaminomethyl, the dimethylaminoethyl and the diethylaminoethylradicals.

Pyrrolidinyl-1-4C-alkyl and piperidinyl-1-4C-alkyl stand for theabovementioned 1-4C-alkyl radicals which are substituted by apyrrolidinyl and piperidinyl radical respectively. Examples which may bementioned are the 2-pyrrolidinoethyl, the 2-piperidinoethyl, thepiperidinomethyl and the 2-(4-piperidin-4-yl)ethyl radicals.

Di-1-4C-alkylaminocarbonyl stands for a radical which, besides thecarbonyl group, contains one of the abovementioned di-1-4C-alkylaminogroups. Examples which may be mentioned are the dimethylcarbamoyl andthe diethylcarbamoyl radicals.

3-7C-Cycloalkyl-1-4C-alkyl stands for one of the abovementioned1-4C-alkyl radicals which is substituted by one of the abovementioned3-7C-cycloalkyl radicals. Examples which may be mentioned are thecyclopropylmethyl, the cyclohexylmethyl and the cyclohexylethylradicals.

1-4C-Alkoxycarbonyl-1-4C-alkyl stands for one of the abovementioned1-4C-alkyl radicals which is substituted by one of the abovementioned1-4C-alkoxycarbonyl radicals. An example which may be mentioned is theethoxycarbonylmethyl radical.

Halo-1-4C-alkyl stands for one of the abovementioned 1-4C-alkyl radicalswhich is substituted by one of the abovementioned halogen atoms. Anexample which may be mentioned is the 3-chloropropyl radical.

Examples which may be mentioned of phenyl radicals substituted by R7, R8and R9 are the 3,4-dihydroxy-, 3-hydroxy-4-methoxy-, 3,4-dimethoxy-,2-methoxy-, 2-ethoxy-, 3-methoxy-, 4-methoxy, 2-hydroxy-, 3-hydroxy-,4-hydroxy-, 3,4-dihydroxy-, 4-acetyl-, 4-fluoro-, 4-chloro-, 2-chloro-,3-chloro-, 3,4-dichloro-, 3-trifluoromethyl-, 2-trifluoromethyl-,2-methyl-, 3-methyl-, 4-methyl-, 2,3-dimethyl-, 2,4-dimethyl-,3,4-dimethyl-, 2,5-dimethyl-, 4-nitro-, 2,6-dinitro-4-trifluoromethyl-and 5-chloro-2-methylaminophenyl radicals.

Examples which may be mentioned of substituted pyrrolidino radicals arethe 2-methoxymethylpyrrolidino, 2-methoxycarbonylpyrrolidino,2-methylpyrrolidino, 2,5-dimethylpyrrolidino, 2-carboxypyrrolidino,4-hydroxy-2-methoxycarbonylpyrrolidino,4-hydroxy-2-ethoxycarbonylpyrrolidino, 2-(2-hydroxyethyl)pyrrolidino,4-hydroxy-2-carboxypyrrolidino, 2-hydroxymethylpyrrolidino,3-hydroxypyrrolidino and the 4-acetoxy-2-carboxypyrrolidino radicals.

Examples which may be mentioned of substituted piperidino radicals arethe 3-hydroxypiperidino, 2-carboxypiperidino, 3-aminopiperidino,4-[2-(4-piperidin-4-yl)ethyl]piperidino, 4-cyano-4-phenylpiperidino,4,4-dihydroxypiperidino, 2-n-propylpiperidino,5-ethyl-2-methylpiperidino, 2-dimethylaminomethylpiperidino,2-(2-pyrrolidinoethyl)piperidino, 4-benzyl-4-hydroxypiperidino,4-formyl-4-phenylpiperidino, 4-hydroxymethyl-4-phenylpiperidino,4-n-propylpiperidino, 4-(3-phenylpropyl)piperidino,4-dimethylaminopiperidino, 4-ethoxy-4-phenylpiperidino,4-hydroxy-4-(4-fluorophenyl)piperidino, 2-(1-hydroxy)benzylpiperidino,2-(1-hydroxy)-4-chlorobenzylpiperidino, 4-(1-pyrrolidinyl)piperidino,4,4-dimethylpiperidino, 4-phenyl-4-propyloxypiperidino,2,6-dimethylpiperidino, 3-hydroxy-2,6-dihydroxymethylpiperidino,2,6-di(2-oxobutyl)piperidino, 4-hydroxypiperidino,4-hydroxy-4-phenylpropylpiperidino, 4-(1-oxopropyl)-4-phenylpiperidino,4-(1-oxobutyl)-4-phenylpiperidino,4-phenyl-4-propyloxycarbonylpiperidino,4-phenyl-4-(1-piperidinylcarbonyl)piperidino,4-carbamoyl-4-phenylpiperidino, 4-carbamoyl-4-dimethylaminopiperidino,4-morpholinocarbonyl-4-phenylpiperidino, 4-carbamoylpiperidino,4-[3-(4-piperidinyl)propyl]piperidino, 2-carboxy-5-hydroxypiperidino,4-acetyl-4-phenylpiperidino, 2-ethyl-2-methylpiperidino,4-ethoxycarbonyl-4-phenylpiperidino, 4-bromo-4-phenylpiperidino,4-carboxy-4-phenylpiperidino,4-hydroxy-4-(3-trifluoromethylphenyl)piperidino, 4-formylpiperidino,4-carboxypiperidino, 4-(4-fluorobenzoyl)piperidino,2-(1,2-dihydroxyethyl)piperidino, 2-(2-dimethylaminoethyl)piperidino,4-(2-dimethylaminoethyl)piperidino, 4-(2-diethylaminoethyl)piperidino,4-(4-chlorobenzoyl)piperidino, 4-(2-butyloxyethyl)-piperidino,4-[2-(1-piperidinyl)ethyl]-piperidino, 2,3-dicarboxypiperidino,2,4-dicarboxypiperidino, 2,6-dicarboxypiperidino, 4-sulfopiperidino,2-ethoxycarbonylpiperidino, 2-methylpiperidino,2,2,6,6-tetramethylpiperidino, 4-hydroxy-2,2,6,6-tetramethylpiperidino,4-amino-2,2,6,6-tetramethylpiperidino, 2,6-dimethylpiperidino,2-hydroxymethylpiperidino, 2-ethylpiperidino,2-(2-hydroxyethyl)piperidino, 3-diethylcarbamoylpiperidino,3-ethoxycarbonylpiperidino, 4-hydroxy-4-(4-chlorophenyl)piperidino,4-(1-piperidinyl)piperidino and the 4-benzylpiperidino radicals.

Examples which may be mentioned of substituted piperazino radicals arethe 4-methylpiperiazino, 4-[2-(2-trifluoromethylphenyl)ethyl]piperazino,4-(3-chloropropyl)piperazino, 4-phenylpiperazino,4-(2-methylphenyl)piperazino, 4-(2,3-dimethylphenyl)piperazino,4-(2-chlorophenyl)piperazino, 4-(2-methoxyphenyl)piperazino,4-(2-ethoxyphenyl)piperazino, 4-(3-chlorophenyl)piperazino,4-(4-fluorophenyl)piperazino, 4-(4-chlorophenyl)piperazino,4-(4-methoxyphenyl)piperazino, 4-carbamoylpiperazino,3-methyl-4-(4-chlorophenyl)piperazino,3-methyl-4-(4-methoxyphenyl)piperazino,3-methyl-4-(4-methylphenyl)piperazino, 4-(2,4-dimethylphenyl)piperazino,4-(3,4-dichlorophenyl)piperazino, 4-(3,4-dimethylphenyl)piperazino,4-(3-hydroxypropyl)piperazino, 3-methyl-4-phenylpiperazino,3-methyl-4-(3-chlorophenyl)piperazino, 4-benzylpiperazino,4-propylpiperazino, 4-(3-methylphenyl)piperazino,4-(3-methoxyphenyl)piperazino, 4-(4-methylphenyl)piperazino,4-(2,5-dimethylphenyl)piperazino, 4-benzhydrylpiperazino,4-cyclopropylpiperazino, 4-cyclobutylpiperazino,4-cyclopentylpiperazino, 4-cyclohexylpiperazino,4-cycloheptylpiperazino, 4-n-butylpiperazino, 4-isobutylpiperazino,4-tert-butylpiperazino, 4-dimethylaminomethylpiperazino,4-(2-diethylaminoethyl)piperazino,4-(3-trifluoromethylphenyl)piperazino, 4-(1-phenylethyl)piperazino,4-ethoxycarbonylmethylpiperazino, 4-(2-phenylethyl)piperazino,4-(2-cyclohexylethyl)piperazino, 4-(2-dimethylaminoethyl)piperazino,4-(2-hydroxyphenyl)piperazino, 4-(3,4-dimethoxyphenyl)piperazino,4-isopropylpiperazino, 3-methyl-4-(3-methoxyphenyl)piperazino,4-(4-hydroxyphenyl)piperazino, 3-methyl-4-(3-methylphenyl)piperazino,4-(3-hydroxyphenyl)piperazino,4-(2,6-dinitro-4-trifluoromethylphenyl)piperazino,4-(1-naphthyl)piperazino, 4-(2-hydroxyethyl)piperazino,4-(4-nitrophenyl)piperazino, 4-(4-acetylphenyl)piperazino,4-ethoxycarbonylpiperazino and the 4-(4-chlorobenzhydryl)piperazinoradicals.

An example which may be mentioned of a substituted morpholino radical isthe 3,5-dimethylmorpholino radical.

Examples which may be mentioned of substituted 1-indolinyl radicals arethe 2-carboxy-1-indolinyl, 6-fluoro-1-indolinyl, 5-bromo-1-indolinyl,2,7-dimethyl-1-indolinyl, 2-methyl-1-indolinyl,5-bromo-7-nitro-1-indolinyl, 5-nitro-1-indolinyl,2,3-dimethyl-1-indolinyl and the 6-nitro-1-indolinyl radicals.

Examples which may be mentioned of substituted1,2,3,4-tetrahydroquinoline radicals are the2-ethoxycarbonyl-1,2,3,4-tetrahydro-1-quinolinyl,2-methyl-1,2,3,4-tetrahydro-1-quinolinyl,6-methyl-1,2,3,4-tetrahydro-1-quinolinyl,6-fluoro-2-methyl-1,2,3,4-tetrahydro-1-quinolinyl,4-methyl-1,2,3,4-tetrahydro-1-quinolinyl,8-amino-1,2,3,4-tetrahydro-1-quinolinyl and the2-fluoro-6-methyl-1,2,3,4-tetrahydro-1-quinolinyl radicals.

Examples which may be mentioned of substituted1,2,3,4-tetrahydroisoquinoline radicals are the1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydro-2-isoquinolinyl,1-(3,4-dihydroxybenzyl)-6,7-dihydroxy-1,2,3,4-tetrahydro-2-isoquinolinyl,3-carboxy-1,2,3,4-tetrahydro-2-isoquinolinyl,6,7-dimethoxy-1,2,3,4-tetrahydro-2-isoquinolinyl,1-benzyl-1,2,3,4-tetrahydro-2-isoquinolinyl,1-(3-hydroxy-4-methoxybenzyl)-6-dimethylamino-1,2,3,4-tetrahydro-2-isoquinolinyl,3-tert-butyl-6-methoxy-4-phenyl-1,2,3,4-tetrahydro-2-isoquinolinyl,1-(3,4-dimethoxybenzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-2-isoquinolinyl,1-(3,4-dihydroxybenzyl)-6,7-dihydroxy-1,2,3,4-tetrahydro-2-isoquinolinyl,6,7-dihydroxy-1,2,3,4-tetrahydro-2-isoquinolinyl,6,7-dimethoxy-1-methyl-1,2,3,4-tetrahydro-2-isoquinolinyl,6,7-dihydroxy-1-methyl-1,2,3,4-tetrahydro-2-isoquinolinyl,6-hydroxy-7-methoxy-1-methyl-1,2,3,4-tetrahydro-2-isoquinolinyl and the1-(5-chloro-2-methylaminophenyl)-1,2,3,4-tetrahydro-2-isoquinolinylradicals.

Suitable salts for compounds of the formula I in which n is the number 0are all acid addition salts. Particular mention may be made of thepharmacologically suitable salts of the inorganic and organic acidswhich are customarily used in pharmaceutical technology.Pharmacologically unsuitable salts which may, for example, be theinitial products of the process for preparing the compounds according tothe invention on an industrial scale are converted intopharmacologically suitable salts by processes known to the skilledperson. Suitable as such are water-soluble and water-insoluble acidaddition salts with acids such as hydrochloric acid, hydrobromic acid,phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid,D-gluconic acid, benzoic acid, 2-(4-hydroxybenzoyl)benzoic acid, butyricacid, sulfosalicylic acid, maleic acid, lauric acid, malic acid, fumaricacid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearicacid, toluenesulfonic acid, methanesulfonic acid or3-hydroxy-2-naphthoic acid, with the acids being used in the preparationof the salts in a ratio of amounts which is equimolar or differstherefrom--depending on whether the acid is monobasic or polybasic anddepending on which salt is required.

For compounds of the formula I in which n is the numbers 1 or 2, alsosuitable as salts are salts with bases. Examples which may be mentionedof basic salts are lithium, sodium, potassium, calcium, aluminum,magnesium, titanium, ammonium, meglumine or guanidinium salts, onceagain the ratio of the amounts of the bases used for preparing thesesalts being equimolar or differing therefrom.

Compounds of the formula I in which R1 is hydrogen, R2 is hydrogen, R3is halogen and n is the number 0, and their salts, are to be emphasized.

Compounds of the formula I in which R1 is hydrogen, R2 is hydrogen, R3is chlorine, R4 is 1-4C-alkyl, A is ethylene or propylene, X is CH and nis the number 0, and their salts, are to be particularly emphasized.

One embodiment within the compounds to be emphasized comprises compoundsof the formula I in which R1 is hydrogen, R2 is hydrogen, R3 is halogen,R4 is 1-4C-alkyl, A is 2-4C-alkylene, X is N or CH and n is the number0, and in which R5 is 1-4C-alkyl or Ar-1-4C-alkyl and R6 isAr-1-4C-alkyl, where Ar is phenyl, furyl or phenyl which is substitutedby R7, R8 and R9, or in which R5 and R6 together represent, withinclusion of the nitrogen atom to which both are bonded, anunsubstituted or substituted heterocyclic ring which is selected fromthe group consisting of piperidine, piperazine,1,2,3,4-tetrahydroquinoline and 1,2,3,4-tetrahydroisoquinoline, where

a substituted piperidino radical is substituted by one or two identicalor different substituents selected from the group consisting of1-4C-alkyl, 1-4C-alkoxy, phenyl, phenyl-1-4C-alkyl and phenylsubstituted by R7, R8 and R9,

a substituted piperazino radical is substituted in position 4 by asubstituent selected from the group consisting of 1-4C-alkyl,1-4C-alkoxycarbonyl, phenyl, phenyl substituted by R7, R8 and R9,phenyl-1-4C-alkyl, phenyl, 1-4C-alkyl substituted by R7, R8 and R9 inthe phenyl radical, and benzhydryl

a substituted 1,2,3,4-tetrahydroquinoline radical is substituted by oneor two identical or different substituents selected from the groupconsisting of 1-4C-alkyl and halogen,

a substituted 1,2,3,4-tetrahydroisoquinoline radical is substituted onthe benzo moiety by one or two substituents selected from the groupconsisting of hydroxyl, 1-4C-alkoxy and di-1-4C-alkylamino, and where

R7 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, halogen or nitro,

R8 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, halogen or nitro, and

R9 is hydrogen or trifluoromethyl,

and the salts of these compounds.

One embodiment within the compounds to be particularly emphasized arecompounds of the formula I in which R1 is hydrogen, R2 is hydrogen, R3is chlorine, R4 is 1-4C-alkyl, A is ethylene or propylene, X is CH and nis the number 0, and in which R5 is 1-4C-alkyl or benzyl and R6 isAr-1-4C-alkyl, where Ar is phenyl or furyl, or in which R5 and R6together represent, with inclusion of the nitrogen atom to which bothare bonded, an unsubstituted or substituted heterocyclic ring which isselected from the group consisting of piperidine, piperazine and1,2,3,4-tetrahydroisoquinoline, where

a substituted piperidino radical is substituted by a substituentselected from the group consisting of phenyl and benzyl,

a substituted piperazino radical is substituted in position 4 by asubstituent selected from the group consisting of phenyl, phenylsubstituted by R7, R8 and R9, and benzyl and

a substituted 1,2,3,4-tetrahydroisoquinoline radical is substituted onthe benzo moiety by one or two 1-4C-alkoxy substituents, and where

R7 is hydrogen or 1-4C-alkoxy,

R8 is hydrogen and

R9 is hydrogen,

and the salts of these compounds.

The invention furthermore relates to a process for the preparation ofthe compounds of the formula I in which R1, R2, R3, R4, R5, R6, X, n andA have the abovementioned meanings, and their salts.

The process comprises

a) reacting mercaptobenzimidazoles of formula II (see appended sheets offormulae) in which R1, R2 and X have the abovementioned meanings withpicoline derivatives III (see appended sheet of formulae) in which R3,R4, R5, R6 and A have the abovementioned meanings, and Y is a suitableleaving group, or comprises

b) reacting compounds of formula IV (see appended sheet of formulae) inwhich R1, R2, R3, R4, X, n and A have the abovementioned meanings, and Zis a suitable leaving group, with amines H--N(R5)R6 and

(if compounds of formula I with n=1 or 2 are the required finalproducts) comprises subsequently oxidizing the compounds with n=0obtained as in a) or b), and/or comprises subsequently, if required,converting the compounds obtained into the salts and/or comprisessubsequently, if required, converting salts obtained into the freecompounds.

In the reaction detailed above, the starting compounds can be used assuch or, where appropriate, in the form of their salts.

Examples of suitable leaving groups Y and Z which may be mentioned arehalogen atoms, especially chlorine, or hydroxyl groups activated byesterification (for example with p-toluenesulfonic acid).

The reaction of II with III takes place in suitable, preferably polarprotic or aprotic solvents (such as methanol, ethanol, isopropanol,dimethyl sulfoxide, acetone, dimethylformamide or acetonitrile) withaddition or with exclusion of water. It is carried out, for example, inthe presence of a proton acceptor. Suitable as, such are alkali metalhydroxides, such as sodium hydroxide; alkali metal carbonates, such aspotassium carbonate; or tertiary amines, such as pyridine, triethylamineor ethyldiisopropylamine. Alternatively, the reaction can also becarried out without a proton acceptor, in which case--depending on thenature of the starting compounds--it is possible where appropriate forthe acid addition salts to be initially separated off in particularlypure form. The reaction temperature can be between 0° and 150° C., withtemperatures between 20° and 80° C. being preferred in the presence ofproton acceptors, and between 60° and 120° C.--especially the boilingpoint of the solvent used--being preferred without proton acceptors. Thereaction times are between 0.5 and 30 hours.

The reaction of the compounds IV with the amines H--N(R5)R6 takes placein a similar way to the reaction of the compounds II with the compoundsIII or, alternatively, preferably without additional solvent, using anexcess of amine as proton acceptor and solvent simultaneously. Thereaction temperature is in this case between 60° and 180° C., preferablybetween 80° and 160° C.

The oxidation of the sulfides (compounds of the formula I with n=0) tothe sulfoxides or sulfones (compounds of the formula I with n=1 or 2)takes place under the conditions familiar to the skilled person foroxidizing sulfides to sulfoxides and sulfones [in this connection, see,for example, J. Drabowicz and M. Mikolajczyk, Organic preparations andprocedures int. 14(1-2), 45-89(1982) or E. Block in S. Patai, TheChemistry of Functional Groups, Supplement E. Part 1, pages 539-608,John Wiley and Sons (Interscience Publication), 1980]. Suitableoxidizing agents are all reagents normally used for oxidizing sulfidesto sulfoxides and sulfones, especially peroxy acids, such as,peroxyacetic acid, trifluoroperoxyacetic acid, 3,5-dinitroperoxybenzoicacid, peroxymaleic acid, magnesium monoperoxyphthalate or, preferably,m-chloroperoxybenzoic acid.

The reaction temperature is (depending on the reactivity of theoxidizing agent and degree of dilution) between -70° C. and the boilingpoint of the solvent used, but preferably between -30° and +20° C.Oxidation with halogens or with hypohalites (for example with aqueoussodium hypochlorite solution) has also proven advantageous, which isexpediently carried out at temperatures between 0° and 50° C. Thereaction is carried out, for example, in inert solvents, for examplearomatic or chlorinated hydrocarbons, such as benzene, toluene,dichloromethane or chloroform, preferably in esters or ethers, such asethyl acetate, isopropyl acetate or dioxane, or in alcohols, preferablyisopropanol.

The sulfoxides according to the invention are optically activecompounds. Further centers of chirality may also be present in themolecule depending on the nature of the substituents. The inventiontherefore embraces both the enantiomers and diastereomers and theirmixtures and racemates. The enantiomers can be separated in a mannerknown per se (for example by preparation and separation of appropriatediastereoisomeric compounds) (see, for example, WO92/08716).

The compounds II are disclosed, for example, in DE 34 04 610 or EP 134400. The compounds III can be prepared, for example, as described in theexamples which follow or in analogy to EP 184 322.

The compounds of the formula IV can be prepared, for example, asdescribed in the examples which follow from starting compounds which areknown or can be obtained in an analogous manner.

The following examples illustrate the invention in detail withoutrestricting it. The compounds according to the invention and thestarting compounds can be prepared in a manner analogous to thedescription in the examples.

EXAMPLES Final products

1.2-{3-Chloro-4-{N-[2-(N-benzyl-N-ethylamino)ethyl]-N-methylamino}-2-pyridyl)-methylthio-1H-benzimidazoletrihydrochloride

2-{3-Chloro-4-[N-(2-chloroethyl)-N-methylamino]-2-pyridyl}-methylthio-1H-benzimidazole(500 mg/1.24 mmol) are heated in N-ethylbenzylamine (15 ml) at 140° C.for 4.5 h. Then the excess N-ethylbenzylamine is removed by distillationunder high vacuum, and the residue is chromatographed on silica gel(dichloromethane/methanol 97/3 mixture which contains 1 ml of conc. NH₃×aq./l). The collected pure fractions are concentrated together in vacuoand dissolved in a little methanol, and saturated ethereal hydrochloricacid (1 ml) and diisopropyl ether are added and the solid whichprecipitates thereby is filtered off and dried in vacuo. Yield: 200 mg(28%) of the title compound as a colorless solid of melting point >180°(decomposition).

2.2-{3-Chloro-4-{N-[2-(1,2,3,4-tetrahydro-2-isoquinolinyl)ethyl]-N-methylamino}-2-pyridyl}-methylthio-1H-benzimidazoletrihydrochloride

2-{3-Chloro-4-[N-2-chloroethyl)-N-methylamino]-2-pyridyl}-methylthio-1H-benzimidazole(500 mg) are heated in 1,2,3,4-tetrahydroisoquinoline (10 ml) at 100° C.for 2.5 h. The excess amine is removed by distillation under highvacuum, and the remaining oily residue is chromatographed on silica gel(petroleum ether/ethyl acetate/methanol 65/30/5-mixture which contains 1ml of conc. NH₃ ×aq./l). The collected pure fractions are concentratedtogether in vacuo and dissolved in a little methanol (5 ml), andethereal hydrochloric acid and then a little diisopropyl ether areadded. The solid which precipitates thereby is filtered off and driedunder high vacuum. Yield: 460 mg (65%) of the title compound as acolorless solid of melting point >240° C. (decomposition).

3.2-{3-Chloro-4-{N-[2-(1,2,3,4-tetrahydro-2-isoquinolinyl)ethyl]-N-methylamino}-2-pyridyl}-methylthio-1H-benzimidazole

2-{3-Chloro-4-{N-[2-(4-1,2,3,4-tetrahydro-2-isoquinolinyl)ethyl]-N-methylamino}-2-pyridyl}-methylthio-1H-benzimidazoletrihydrochloride (0.1 g) is dissolved in water (7 ml), and a saturatedsolution of aqueous sodium bicarbonate (1 ml). is added. The colorlessprecipitate produced thereby is filtered off, washed with distilledwater and dried at 60° C. under high vacuum. Yield: 70 mg (87%) of thetitle compound of melting point >88° C. (decomposition).

4.2-{3-Methyl-4-{N-{2-[N-(2-furfuryl)-N-methylamino]-ethyl}-N-methylamino}-2-pyridyl}-methylthio-1H-benzimidazoletrihydrochloride

In analogy to Example 1, 1.35 g (64%) of the title compound are obtainedwith a melting point of 212° C. (decomposition) by reacting2-{3-chloro-4-[N-2-chloroethyl)-N-methylamino]-2-pyridyl}methylthio-1H-benzimidazole(1.5 g) with N-furfurylmethylamine (2 ml) after heating at 100° C. for 4hours.

5.2-{3-Chloro-4-{N-[2-(1,2,3,4-tetrahydro-2-isoquinolinyl)ethyl]-N-methylamino)-2-pyridyl}-methylthio-1H-imidazo[5,4-b]pyridine

The title compound is obtained as a colorless powder of melting point128°-129° C. (52%) by the procedure indicated in Example 2 starting from2-{3-chloro-4-[N-(2-chloroethyl)-N-methylamino]-2-pyridyl}-methylthio-1H-imidazo[5,4-b]pyridineand 1,2,3,4-tetrahydroisoquinoline after chromatography on silica gel(ethyl acetate/methanol 4/1).

6.2-{3-Chloro-4-{N-[2-(N-benzyl-N-methylamino)-ethyl]-N-methylamino}-2-pyridyl}-methylthio-1H-benzimidazoletrihydrochloride

The title compound is obtained as an amorphous powder of melting point237°-240° C. (decomposition) by the procedure indicated in Example 1, byreacting2-{3-chloro-4-[N-(2-chloroethyl)-N-methylamino]-2-pyridyl}-methylthio-1H-benzimidazolewith N-methylbenzylamine and after purification on silica gel andsubsequent conversion into the trichloride.

7.2-{3-Chloro-4-{N-[2-(N,N-dibenzylamino)-ethyl]-N-methylamino}-2-pyridyl}-methylthio-1H-benzimidazoletrihydrochloride

The title compound is obtained as a colorless amorphous powder ofmelting point oil by the procedure indicated in Example 2, by reacting2-{3-chloro-4-[N-(2-chloroethyl)-N-methylamino]-2-pyridyl}-methylthio-1H-benzimidazolewith dibenzylamine after chromatography on silica gel (petroleumether/ethyl acetate 1/1).

8.2-{3-Chloro-4-{N-[2-(N,N-diethylamino)-ethyl]-N-methylamino}-2-pyridyl}-methylthio-1H-benzimidazoletrihydrochloride

The title compound is obtained as an amorphous powder of melting point245.7° C. (decomposition) by the procedure indicated in Example 1, byreacting2-{3-chloro-4-[N-2-chloroethyl)-N-methylamino]-2-pyridyl}-methylthio-1H-benzimidazolewith diethylamine after chromatography on silica gel (ethylacetate/methanol 4/1) and subsequent conversion into thetrihydrochloride.

9.2-{3-Chloro-4-{N-[2-(N-methyl-N-phenethylamino)-ethyl]-N-methylamino}-2-pyridyl}-methylthio-1H-benzimidazoletrihydrochloride

The title compound is obtained as an amorphous powder of melting point239°-241° C. (decomposition) by the procedure indicated in Example 1, byreacting2-{3-chloro-4-[N-(2-chloroethyl)-N-methylamino]-2-pyridyl}-methylthio-1H-benzimidazolewith N-methylphenethylamine after purification on silica gel (ethylacetate/methanol 9/1) and subsequent conversion into thetrihydrochloride.

10.2-{3-Chloro-4-{N-[2-(N-furfuryl-N-methylamino)ethyl]-N-methylamino}-2-pyridyl}-methylthio-1H-benzimidazoletrihydrochloride

The title compound is obtained as a brownish amorphous powder of meltingpoint 239°-241° C. (decomposition) by the procedure indicated in Example1, by reacting2-{3-chloro-4-[N-(2-chloroethyl)-N-methylamino]-2-pyridyl}-methylthio-1H-benzimidazolewith N-furfurylmethylamine after chromatography on silica gel (ethylacetate/methanol 9/1) and subsequent conversion into thetrihydrochloride.

11.2-{3-Chloro-4-{N-[2-(4-phenyl-piperidino)-ethyl]-N-methylamino}-2-pyridyl}-methylthio-1H-benzimidazole

The title compound is obtained as an amorphous yellowish powder ofmelting point 55°-65° C. by the procedure indicated in Example 2, byreacting2-{3-chloro-4-[N-(2-chloroethyl)-N-methylamino]-2-pyridyl}-methylthio-1H-benzimidazolewith 4-phenylpiperidine after purification on silica gel (ethylacetate/methanol 3/1).

12.2-{3-Chloro-4-{N-[2-[4-benzyl-piperidino)-ethyl]-N-methylamino}-2-pyridyl}-methylthio-1H-benzimidazole

The title compound is obtained as a viscous, yellowish oil by theprocedure indicated in Example 2, by reacting2-{3-chloro-4-[N-(2-chloroethyl)-N-methylamino]-2-pyridyl}-methylthio-1H-benzimidazolewith 4-benzylpiperidine after purification on silica gel (ethylacetate/methanol 4/1).

13.2-{3-Chloro-4-[N-(2-piperidinoethyl)-N-methylamino]-2-pyridyl}-methylthio-1H-benzimidazole

The title compound is obtained as a viscous brownish oil by theprocedure indicated in Example 2, by reacting2-{3-chloro-4-[N-(2-chloroethyl)-N-methylamino]-2-pyridyl}-methylthio-1H-benzimidazolewith piperidine after chromatography on silica gel (ethylacetate/methanol 4/1).

14.2-{3-Chloro-4-{N-[2-(6,7-dimethoxy-1,2,3,4-tetrahydro-2-isoquinolinyl)ethyl]-N-methylamino}-2-pyridyl}-methylthio-1H-benzimidazole

The title compound is obtained as a viscous yellowish oil by theprocedure indicated in Example 2, by reacting2-{3-chloro-4-[N-(2-chloroethyl)-N-methylamino]-2-pyridyl}-methylthio-1H-benzimidazolewith 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline after chromatographyon silica gel (ethyl acetate/methanol 4/1).

15.2-{3-Chloro-4-{N-[2-(4-phenylpiperazino)-ethyl]-N-methylamino}-2-pyridyl}-methylthio-1H-benzimidazolehydrochloride

The title compound is obtained as an amorphous powder of melting point212°-215° C. (decomposition) by the procedure indicated in Example 1, byreacting2-{3-chloro-4-[N-(2-chloroethyl)-N-methylamino]-2-pyridyl}-methylthio-1H-benzimidazolewith 4-phenylpiperazine after chromatography on silica gel (ethylacetate/methanol 4/1) and subsequent conversion into the hydrochloride.

16.2-{3-Chloro-4-{N-[2-(4-benzylpiperazino)-ethyl]-N-methylamino}-2-pyridyl}-methylthio-1H-benzimidazoletrihydrochloride

The title compound is obtained as an amorphous powder of melting point227°-230° C. (decomposition) by the procedure indicated in Example 1, byreacting2-{3-chloro-4-[N-(2-chloroethyl)-N-methylamino]-2-pyridyl}-methylthio-1H-benzimidazolewith 4-benzylpiperazine after chromatography on silica gel (ethylacetate/methanol 4/1) and subsequent conversion into thetrihydrochloride.

17.2-{3-Chloro-4-{N-[2-(4-(2-methoxyphenyl)-piperazino)-ethyl]-N-methylamino}-2-pyridyl}-methylthio-1H-benzimidazoletrihydrochloride

The title compound is obtained as a viscous oil by the procedureindicated in Example 1, by reacting2-{3-chloro-4-[N-(2-chloroethyl)-N-methylamino-2-pyridyl}-methylthio-1H-benzimidazolewith 4-(2-methoxyphenyl)piperazine after purification on silica gel(ethyl acetate/methanol 9/1).

18.2-{3-Chloro-4-{N-[3-(1,2,3,4-tetrahydro-2-isoquinolinyl)-propyl]-N-methylamino}-2-pyridyl}-methylthio-1H-benzimidazoletrihydrochloride

The title compound of melting point 239°-240° C. (decomposition) isobtained in analogy to Example 2 by reacting2-{3-chloro-4-[N-(3-chloropropyl)-N-methylamino]-2-pyridyl}-methylthio-1H-benzimidazolewith 1,2,3,4-tetrahydroisoquinoline and conversion into thetrihydrochloride.

19.2-{3-Chloro-4-{N-[3-(N-benzyl-N-methylamino)propyl]-N-methylamino}-2-pyridyl}-methylthio-1H-benzimidazoletrihydrochloride

The title compound is obtained as an amorphous powder of melting point228°-230° C. (decomposition) by the procedure indicated in Example 1, byreacting2-{3-chloro-4-[N-(3-chloropropyl)-N-methylamino]-2-pyridyl}-methylthio-1H-benzimidazolewith N-methylbenzylamine after purification on silica gel and subsequentconversion into the trihydrochloride.

20.2-{3-Chloro-4-{N-[3-(6,7-dimethoxy-1,2,3,4-tetrahydro-2-isoquinolinyl)-propyl]-N-methylamino}-2-pyridyl}-methylthio-1H-benzimidazoletrihydrochloride

The title compound is obtained as a viscous yellowish oil by theprocedure indicated in Example 1, by reacting2-{3-chloro-4-[N-(3-chloropropyl)-N-methylamino]-2-pyridyl)-methylthio-1H-benzimidazolewith 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline after chromatographyon silica gel (petroleum ether/ethyl acetate/methanol 2/5/1).

21.2-{3-Chloro-4-{N-[3-(4-benzyl-piperidino)-propyl]-N-methylamino}-2-pyridyl}-methylthio-1H-benzimidazoletrihydrochloride

The title compound is obtained as a viscous, yellowish oil by theprocedure indicated in Example 1, by reacting2-{3-chloro-4-[N-(3-chloropropyl)-N-methylamino]-2-pyridyl}-methylthio-1H-benzimidazolewith 4-benzylpiperidine after purification on silica gel (ethylacetate/methanol 4/1) and conversion into the trihydrochloride.

Precursors A.2-{3-Chloro-4-[N-(2-chloroethyl)-N-methylamino]-2-pyridyl}-methylthio-1H-benzimidazoledihydrochloride

1) 3-Chloro-4-[N-(2-hydroxyethyl)-N-methylamino]-2-hydroxymethylpyridine

A mixture of 3,4-dichloro-2-hydroxymethylpyridine (J. Med. Chem. 1989,32, 1970) (2.5 g) in 2-methylaminoethanol (30 ml) is heated at 160° C.in a steel autoclave for 2.5 h, the excess amine is stripped off underhigh vacuum, and the remaining residue is chromatographed on silica gel(dichloromethane/methanol 95/5). Yield: 2.3 g as yellowish oil.

2) 3-Chloro-4-[N-(2-chloroethyl)-N-methylamino]-2-chloromethylpyridinehydrochloride

A solution of thionyl chloride (4 ml) in dichloromethane (20 ml) isadded dropwise to a solution of3-chloro-4-[N-(2-hydroxyethyl)-N-methylamino]-2-hydroxymethylpyridine(2.3 g) in dichloromethane (30 ml) at 0° C. The temperature is thenallowed to rise to 20° C. (20 min), and then the temperature is kept at40° C. for 30 min. The solvent is stripped off in vacuo and then theremaining residue is chromatographed on silica gel (petroleumether/ethyl acetate 7/3 mixture which contains 1 ml of conc. NH₃ ×aq/l).Yield: 2.6 g.

3) A mixture of 2-mercapto-1H-benzimidazole (1.8 g) and3-chloro-4-[N-(2-chloroethyl)-N-methylamino]-2-chloromethylpyridinehydrochloride (1.1 g) in isopropanol (40 ml) is boiled for 1.5 h, thesolvent is stripped off in vacuo until the volume is 20 ml, anddiisopropyl ether (20 ml) is added to this solution. The crystals whichprecipitate after some time are filtered off and dried in vacuo. Yield:1.2 g of the title compound of melting point 202° C. (decomposition).

2-{3-Chloro-4-[N-(3-chloropropyl)-N-methylamino]-2-pyridyl}-methylthio-1H-benzimidazoledihydrochloride is obtained in an analogous manner.

B.2-{3-Chloro-4-[N-(2-chloroethyl)-N-methylamino]-2-pyridyl}-methylthio-1H-imidazo[5,4-b]pyridine

A mixture of3-chloro-4-[N-(2-chloroethyl)-N-methylamino]-3-chloromethylpyridinehydrochloride (0.96 g) and 2-mercapto-1H-imidazo[5,4-b]pyridine (0.5 g)in isopropanol (25 ml) is heated at 90° C. for 4 h, and the reactionmixture is then cooled to 0° C. The crystals which have precipitated arefiltered off and washed with a little cold isopropanol. The filter cakeis dissolved in water (30 ml), saturated aqueous sodium bicarbonatesolution (20 ml) is added to the solution, and the mixture is extractedwith dichloromethane. The collected extracts are evaporated to drynessin vacuo, and the remaining crystalline residue is dried under highvacuum. Yield: 0.68 g of the title compound of melting point 184°-185°C.

Susceptibility of Industrial Application

The excellent activity of compounds of the formula I and their salts onhelicobacter bacteria makes it possible for them to be used in humanmedicine as active substances for the treatment of diseases based onhelicobacter bacteria.

The invention therefore furthermore relates to a method for thetreatment of mammals, especially humans, suffering from diseases basedon helicobacter bacteria. The method comprises administering atherapeutically effective and pharmacologically suitable amount of oneor more compounds of formula I and/or of their pharmacologicallysuitable salts to the individual with the disease.

The invention additionally relates to the compounds of the formula I andtheir pharmacologically suitable salts for use for the treatment ofdiseases based on helicobacter bacteria.

The invention likewise embraces the use of compounds of formula I and oftheir pharmacologically suitable salts for producing pharmaceuticalsused to control diseases based on helicobacter bacteria.

The invention furthermore relates to pharmaceuticals for controllinghelicobacter bacteria, which contain one or more compounds of thegeneral formula I and/or their pharmacologically suitable salts.

Of the helicobacter strains on which the compounds of the formula Iprove to be effective, particular mention may be made of the strainHelicobacter pylori.

The pharmaceuticals are produced by processes known per se and familiarto the skilled person. As pharmaceuticals, the pharmacologically activecompounds of the formula I and their salts (=active substances) are usedeither as such or, preferably, in combination with suitablepharmaceutical ancillary substances, for example in the form of tablets,coated tablets, capsules, emulsions, suspensions, gels or solutions,where the content of active substance is preferably between 0.1 and 95%.

The ancillary substances suitable for the required pharmaceuticalformulations are familiar to the skilled person on the basis of hisexpert knowledge. Besides solvents, gel formers, tablet ancillarysubstances and other active substance vehicles, it is possible to use,for example, antioxidants, dispersants, emulsifiers, antifoam agents,masking flavors, preservatives, solubilizers, colorants or permeationpromoters and complexing agents (for example cyclodextrins).

The active substances can be administered, for example, parenterally(for example intravenously) or, in particular, orally.

In general, the active substances are administered in human medicine ina daily dose of about 0.2 to 50, preferably 1 to 30, mg/kg ofbodyweight, where appropriate in the form of several, preferably 2 to 6,individual doses to achieve the desired result.

In this connection, it should particularly be mentioned as an aspectessential to the invention that the compounds of the formula I in whichn is the number 0 prove to be active on helicobacter bacteria even onadministration of doses which are below the doses which would have to beused to achieve an inhibition--sufficient for therapeutic purposes--ofgastric acid secretion.

Compounds of the formula I in which n is the number 1 also have--besidestheir activity on helicobacter bacteria--a pronounced inhibitory effecton gastric acid secretion. Accordingly, these compounds can also be usedto treat diseases based on increased gastric acid secretion.

Biological Investigations

The compounds of the formula I were investigated for their activity onHelicobacter pylori by methods based on those described by TomoyukiIwahi et al. (Antimicrobial. Agents and Chemotherapy, 1991, 490-496)using Columbia agar (Oxoid) and with a growth period of 4 days. Theinvestigated compounds were found thereby to have the MIC values listedin the following table (the stated numbers of the compounds agree withthe compound numbers in the description).

                  TABLE                                                           ______________________________________                                        Compound      MIC-Value                                                       No.           (μg/ml)                                                      ______________________________________                                         1            <1                                                               2            <1                                                               3            <1                                                               4            <1                                                               5            <1                                                               6            <1                                                               9            <1                                                              10            <1                                                              11            <1                                                              12            <1                                                              13            <1                                                              14            <1                                                              15            <1                                                              16            <1                                                              17            <1                                                              18            <1                                                              19            <1                                                              20            <1                                                              21            <1                                                              ______________________________________                                         ##STR2##

I claim:
 1. A compound of formula Iin which R1 is hydrogen, 1-4C-alkyl,1-4C-alkoxy, halogen, trifluoromethyl, wholly or predominantlyfluorine-substituted 1-4C-alkoxy, chlorodifluoromethoxy or2-chloro-1,1,2-trifluoroethoxy, R2 is hydrogen or 1-4C-alkyl, R3 ishalogen or 1-4C-alkyl, R4 is 1-7C-alkyl, A is 1-7C-alkylene, X is N orCH, and n is the number 0, 1 or 2,and in which R5 is 1-7C-alkyl,3-8C-cycloalkyl or Ar-1-4C-alkyl and R6 is 1-7C-alkyl, 3-8C-cycloalkylor Ar-1-4C-alkyl,where Ar is phenyl, furyl, naphthyl,tetrahydronaphthyl, or phenyl which is substituted by R7, R8 and R9,orin which R5 and R6 together represent, with inclusion of the nitrogenatom to which both are bonded, an unsubstituted or substitutedheterocyclic ring which is selected from the group consisting ofpyrrolidine, piperidine, piperazine, morpholine, indoline,octahydro-1H-indole, 1,2,3,4-tetrahydroquinoline,1,2,3,4-tetrahydroisoquinoline, decahydroquinoline anddecahydroisoquinoline,where a substituted pyrrolidino radical issubstituted by one or two identical or different substituents selectedfrom the group consisting of 1-4C-alkyl, 1-4C-alkoxy,1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxycarbonyl, 1-4C-alkylcarbonyloxy,hydroxy-1-4C-alkyl, hydroxyl and carboxyl, a substituted piperidinoradical is substituted by one, two or three identical or differentsubstituents selected from the group consisting of 1-4C-alkyl,gem.-di-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl,1-4C-alkoxycarbonyl, 1-4C-alkylcarbonyl, 1-4C-alkylcarbonyl-1-4C-alkyl,hydroxy-1-4C-alkyl, dihydroxy-1-4C-alkyl, di-1-4C-alkylamino,di-1-4C-alkylamino-1-4C-alkyl, pyrrolidino, piperidino,pyrrolidinyl-1-4C-alkyl, piperidinyl-1-4C-alkyl, carbamoyl,di-1-4C-alkylaminocarbonyl, piperidinocarbonyl, morpholinocarbonyl,phenyl, phenyl substituted by R7, R8 and R9, phenyl-1-4C-alkyl, benzoyl,benzoyl substituted by halogen, or formyl, carboxyl, cyano, hydroxyl,halogen and sulfo, a substituted piperazino radical can be substitutedin position 2, 3, 5 or 6 by a 1-4C-alkyl radical and is substituted inposition 4 by a substituent selected from the group consisting of1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl,1-4C-alkoxycarbonyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, hydroxy-1-4C-alkyl,di-1-4C-alkylamino-1-4C-alkyl, halo-1-4C-alkyl, carbamoyl, phenyl,phenyl substituted by R7, R8 and R9, phenyl-1-4C-alkyl,phenyl-1-4C-alkyl substituted by R7, R8 and R9 in the phenyl radical,naphthyl, benzhydryl and benzhydryl substituted by halogen, asubstituted morpholino radical is substituted by one or two identical ordifferent 1-4C-alkyl radicals, a substituted 1-indolinyl radical can besubstituted in position 2 and/or 3 by a carboxyl group or by one or twoidentical or different 1-4C-alkyl radicals, and can be substituted inthe benzo moiety by one or two identical or different substituentsselected from the group consisting of 1-4C-alkyl, halogen and nitro, asubstituted 1,2,3,4-tetrahydroquinoline radical is substituted by one ortwo identical or different substituents selected from the groupconsisting of 1-4C-alkyl and halogen, a substituted1,2,3,4-tetrahydroisoquinoline radical can be substituted on positions1, 3 and/or 4 by one or two identical or different substituents selectedfrom the group consisting of 1-4C-alkyl, carboxyl, phenyl,phenyl-1-4C-alkyl or phenyl which is substituted by R7, R8 and R9 in thephenyl radical, and can be substituted on the benzo moiety by one or twosubstituents selected from the group consisting of hydroxyl, 1-4C-alkoxyand di-1-4C-alkylamino,and where R7 is hydrogen, 1-4C-alkyl,1-4C-alkoxy, 1-4C-alkylcarbonyl, halogen, 1-4C-alkylamino or nitro, R8is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, halogen or nitro,and R9 ishydrogen or trifluoromethyl,or a salt thereof.
 2. A compound of formulaI as claimed in claim 1, in which R1 is hydrogen, R2 is hydrogen, R3 ishalogen and n is the number 0, or a salt thereof.
 3. A compound offormula I as claimed in claim 1, in which R1 is hydrogen, R2 ishydrogen, R3 is chlorine, R4 is 1-4C-alkyl, A is ethylene or propylene,X is CH and n is the number 0, or a salt thereof.
 4. A compound of theformula I as claimed in claim 1, in which R1 is hydrogen, R2 ishydrogen, R3 is halogen, R4 is 1-4C-alkyl, A is 2-4C-alkylene, X is N orCH and n is the number 0, and in which R5 is 1-4C-alkyl or Ar-1-4C-alkyland R6 is Ar-1-4C-alkyl, where Ar is phenyl, furyl or phenyl which issubstituted by R7, R8 and R9, or in which R5 and R6 together represent,with inclusion of the nitrogen atom to which both are bonded, anunsubstituted or substituted heterocyclic ring which is selected fromthe group consisting of piperidine, piperazine,1,2,3,4-tetrahydroquinoline and 1,2,3,4-tetrahydroisoquinoline, whereasubstituted piperidino radical is substituted by one or two identical ordifferent substituents selected from the group consisting of 1-4C-alkyl,1-4C-alkoxy, phenyl, phenyl-1-4C-alkyl and phenyl substituted by R7, R8and R9, a substituted piperazino radical is substituted in position 4 bya substituent selected from the group consisting of 1-4C-alkyl,1-4C-alkoxycarbonyl, phenyl, phenyl substituted by R7, R8 and R9,phenyl-1-4C-alkyl, phenyl-1-4C-alkyl substituted by R7, R8 and R9 in thephenyl radical, and benzhydryl a substituted 1,2,3,4-tetrahydroquinolineradical is substituted by one or two identical or different substituentsselected from the group consisting of 1-4C-alkyl and halogen, asubstituted 1,2,3,4-tetrahydroisoquinoline radical is substituted on thebenzo moiety by one or two substituents selected from the groupconsisting of hydroxyl, 1-4C-alkoxy and di-1-4C-alkylamino, and where R7is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, halogen or nitro, R8 is hydrogen,1-4C-alkyl, 1-4C-alkoxy, halogen or nitro, and R9 is hydrogen ortrifluoromethyl,or a salt thereof.
 5. A compound of formula I as claimedin claim 1, in which R1 is hydrogen, R2 is hydrogen, R3 is chlorine, R4is 1-4C-alkyl, A is ethylene or propylene, X is CH and n is the number0, and in which R5 is 1-4C-alkyl or benzyl and R6 is Ar-1-4C-alkyl,where Ar is phenyl or furyl, or in which R5 and R6 together represent,with inclusion of the nitrogen atom to which both are bonded, anunsubstituted or substituted heterocyclic ring which is selected fromthe group consisting of piperidine, piperazine and1,2,3,4-tetrahydroisoquinoline, wherea substituted piperidino radical issubstituted by a substituent selected from the group consisting ofphenyl and benzyl, a substituted piperazino radical is substituted inposition 4 by a substituent selected from the group consisting ofphenyl, phenyl substituted by R7, R8 and R9, and benzyl and asubstituted 1,2,3,4-tetrahydroisoquinoline radical is substituted on thebenzo moiety by one or two 1-4C-alkoxy substituents, and where R7 ishydrogen or 1-4C-alkoxy, R8 is hydrogen and R9 is hydrogen,or a saltthereof.
 6. A process for the preparation of a compound of formula I asclaimed in claim 1, in which R1, R2, R3, R4, R5, R6, X, n and A have themeanings stated in claim 1, and a salt thereof, which comprisesa)reacting a mercaptobenzimidazole of the formula II ##STR3## in which R1,R2 and X have the meanings stated in claim 1, with a picoline derivativeIII ##STR4## in which R3, R4, R5, R6 and A have the meanings stated inclaim 1, and Y is a suitable leaving group, or comprises b) reacting acompound of the formula IV ##STR5## in which R1, R2, R3, R4, X, n and Ahave the meanings stated in claim 1, and Z is a suitable leaving group,with an amine H--N(R5)R6 and(if a compound of the formula I with n=1 or2 is the required final product) comprises subsequently oxidizing thecompound with n=0 obtained as in a) or b), and/or comprisessubsequently, if required, converting the compound obtained into a saltthereof and/or comprises subsequently, if required, converting a saltobtained into the free compound.
 7. A pharmaceutical comprising one ormore compounds of formula I as claimed in claim 1 and/orpharmacologically suitable salt thereof.
 8. A pharmaceutical compositioncomprising a suitable carrier and an effective amount of a compound ofclaim 1 or a pharmacologically suitable salt thereof.
 9. In a method forcontrolling Helicobacter bacteria with an effective amount of an activeingredient, the improvement wherein the active ingredient is a compoundof claim 1 or a pharmacologically suitable salt thereof.
 10. In a methodfor treatment and/or prophylaxis of a disorder of the stomach and/or ofthe intestine with an effective amount of an active ingredient, theimprovement wherein the active ingredient is a compound of claim 1 or apharmacologically suitable salt thereof.
 11. A method for treatmentand/or prophylaxis of a disorder of the stomach and/or of the intestinebased on increased gastric acid secretion, which comprises administeringto a subject, prone to or afflicted with such disorder, an effectiveamount of a compound of claim 1, in which n is the number 1, or apharmacologically suitable salt thereof.